The usefulness and importance of biologically active compounds which contain beta-lactam bonds is well established. This class of compounds includes the well-known penicillin and cephalosporin families of antibiotics. The synthetic production of these compounds presents many of the problems normally attendant to complex organic synthesis which include the challenge of designing a synthetic strategy to maximize yield of the desired product. As a general rule, it is desirable to find synthetic strategies which will minimize the number of synthetic steps and to have those synthetic steps, where possible, favor the production of the desired compound having the desired isomeric form where more than one such isomeric form exists. This is especially critical to the synthetic production of biologically active compounds whose activity very often depends on the compound's stereoisomerism.
Because of the delicate nature of biologically active compounds (or their precursors), the synthesis of these compounds is most advantageously carried out under mild reaction conditions. Mild reaction conditions can also be important in preventing unwanted side reactions as well as preventing the racemization of products from stereoselective synthetic steps.
In particular, the production of the biologically active compounds (i.e. penicillin and cephalosporin antibiotics and the like) presented here presents two problems. The first problem is the stereoselective formation of the precursor by the reaction of a carbonyl group (i.e. the carbonyl pended at the 4-position of the 2,5-oxazolidinedione) with a suitable thiol amine. The second problem is that a carboxylic acid moiety must be available to form an intramolecular beta-lactam bond while maintaining the desired stereochemistry of the final product.
In addition, it is desirable to develop synthetic strategies which produce fewer steps and by-products in order to avoid unwanted side reactions, as well as to produce a purer product without extensive filtration or recrystalization.
Several methods of producing compounds in the penicillin and cephalosporin families are already known in the art. Examples include Sheehan, J. C. and Henery-Logan, K. R. The Total and Partial General Synthesis of The Penicillins, J. Am. Chem. Soc., Vol. 18, pp. 2983-2990 (1961); Aizpurua, J. M. et al., A Convenient Synthetic Approach to Alpha-Amino-Beta-Lactam Synthesis Promoted By Phenol Diclorophosphate Reagent, Tetrahedron Letters, Vol. 25, No. 35, pp. 3905-3908 (1984); Evans, D. A. and Sjorgren, E. B., The Asymmetric Synthesis of Beta-Lactam Antibiotics - I Application of Chiral Oxazolidones in the Staudinger Reaction, Tetrahedron Letters, Vol. 26, No. 32, pp. 3783, 3786 (1985); Evans, D. A. and Sjogren, E. B., The Asymmetric Synthesis of Beta-Lactam Antibiotics - II The First Enantio Selective Synthesis of the Carbacephalosporin Nucleus, Tetrahedron Letters, Vol. 26, No. 32, pp. 3787-3790 (1985); and Wei, C. C., Synthesis of Chiral Beta-Lactams Using L-Ascorbic Acid , J. Org. Chem., Vol. 50, pp. 3462-3467 (1985). An example of a cephalosporin synthesis is contained in Woodward et al. Total Synthesis, J. Am. Chem. Soc. 88, 852 (1966). A review of cephalosporin C and related compounds is also contained in Abraham, Quart. Rev. Chem. Soc. 21, 231 (1967). A general resource material on these types of syntheses is Coppola, G. M. and Schuster, H. F. Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids, John Wiley & Sons (1987). All of the above publications are incorporated herein by reference.
The synthetic pathways described in these and other prior art references typically involve a multi-step synthesis (i.e. typically more than 10 steps) which produce many varied by-products and always involve the extensive utilization of blocking groups to prevent unwanted side reactions and direct the synthesis towards the desired product.
It has now been found that the novel 4-[1-oxoalkyl]-2,5-oxazolidinediones can be applied in a variety of synthetic schemes to accomplish the desired stereoselective synthesis via a small number of synthetic steps without the need for the extensive use of blocking groups to protect reactive moieties of the precursors (i.e. the lactam-forming amino group) during preceeding synthetic steps (i.e. the thiazolidine-forming step). Furthermore, the small amount of "blocking" which is done in the method of the present invention produces relatively small amounts of non-contaminating by-products. The method of the present invention can be carried out under mild reaction conditions to prevent loss of product due to the decomposition or racemization, resulting in relatively high end product yields.